Flocculated suspension of megestrol acetate

ABSTRACT

A novel oral pharmaceutical composition in the form of a stable flocculated suspension in water is described as comprising: megestrol acetate; at least one compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and sorbitol; and a surfactant, wherein polysorbate and polyethylene glycol are not simultaneously present.

FIELD OF THE INVENTION

[0001] The present invention relates to a composition containingmegestrol acetate which is the generic name for17-α-acyloxy-6-methylpregna-4,6 diene-3,20-dione.

BACKGROUND OF THE INVENTION

[0002] Megestrol acetate is a steroid compound known for itsanti-neoplastic activity.

[0003] Kirk et al., U.S. Pat. No. 3,356,573, disclose a megestrolacetate pharmaceutical tablet preparation comprising lactose, magnesiumstearate and starch. Kirk, et al, also disclose that liquid compositionsof megestrol acetate can be useful but provided no details as to thecomposition of such formulations.

[0004] Petrow et al., U.S. Pat. No. 4,396,615, disclose a method oftreating androgen-related disorders by administering6-methyleneprogesterone derivatives concurrently with megestrol acetate.However, Petrow et al. but do not elaborate on what constitutes themegestrol acetate formulation.

[0005] Greaney et al., U.S. Pat. No. 4,370,321, disclose adjuvanttherapy for the treatment of breast cancer employing megestrol acetate.However, the type or composition of the megestrol acetate formulation isnot specifically described.

[0006] Labrie, U.S. Pat. No. 4,666,885, discloses combination therapyfor treatment of female breast cancer comprising the administration ofluteinizing hormones in combination with an anti-androgen compound suchas megestrol acetate. In particular, Labrie discloses that theanti-androgens are formulated with conventional pharmaceuticalexcipients (e.g., spray dried lactose and magnesium stearate) intotablets or capsules for oral administration.

[0007] Labrie, U.S. Pat. No. 4,760,053 discloses methods of treating sexsteroid dependent cancers by combination therapy which includes the useof megestrol acetate. However, Labrie does not describe the type orcomposition of pharmaceutical formulation used in the treatment.

[0008] Labrie, U.S. Pat. No. 4,775,661, discloses methods of treatingfemale breast cancer with a combination therapy in which megestrolacetate is disclosed as a suitable steroidal anti-androgen. Labrie alsodiscloses that megestrol acetate, as an active substance, may be mixedwith binders such as polyethylene glycol and may include taste improvingsubstances which can be worked into tablets or dragee cores.

[0009] Since the use of megestrol acetate is widespread in clinicalmedicine, it would be desirable to have a liquid pharmaceutical dosagein a flocculated form for use in those cases where patients are unableto swallow tablets or capsules or where a high dose would require theingestion of a relatively large number of tablets. Unfortunately, theformulation of a flocculated suspension which is stable is difficult inthe case of megestrol acetate.

[0010] Atzinger et al., U.S. Pat. No. 5,338,732, point out thedistinction between a flocculated suspension and suspensions in generaland point out that the stability of a flocculated suspension of asteroid such as megestrol acetate can be critically dependent onconcentration. Furthermore, they also disclose that megestrol acetateflocculated suspensions are unique because what would otherwise bepredictable based on the prior art teachings does not apply when thedrug is megestrol acetate. For instance, it is well known in the artprior to Atzinger et al. that megestrol acetate, a hydrophobic solid, isnot easily wetted by water and has a relatively high interfacial tensionaccentuated by entrapped air absorbed on the surface of the particle.Hence, the use of surfactants are required to provide a suspension andmaintain physical stability. According to Atzinger et al., the amountand type of surfactants are particularly critical in providing a stablefloc. The flocculated suspension of megestrol acetate of Atzinger et al.uses megestrol acetate micronized so that 90% of the weight of particlesis below 20 microns and the mass median diameter is between 3.0 and 10microns, and requires that the micronized particles are dispersed inwater with polysorbate 80 and polyethylene glycol to reduce interfacialtension between the particle, entrapped gas and water.

[0011] According to R. A. Nash, Chap. 5, page 181, (PharmaceuticalSuspensions, Pharmaceutical Dosage Forms, Marcel Decker, N.Y.) the usualconcentration of a surfactant varies from 0.05 to 0.5% w/v and dependson the solids content intended for suspension. Examples of suchsuspensions are given in Table 1 which lists some currently marketedsteroid suspensions (1989 Physicians Desk Reference, 43rd Edition) andthe polysorbate 80 surfactant concentration. TABLE 1 Percent ofPolysorbate 80 Concentration Used in Steroid Suspensions According toR.A. Nash, Chap. 5, page 181, (Pharmaceutical Suspensions,Pharmaceutical Dosage Forms, Marcel Decker, New York) Steroid Conc.Polysorbate 80 Steroid mg/ml percent w/v Aristocort Forte 40 0.2Artistospan 20 0.4  5 0.2 Cortone Acetate 25 to 50 0.4 Decadron-LA 80.075 Depo-Provera 100  0.184 Hydeltra-T.B.A. 20 0.1 HydrocortoneAcetate 25 to 50 0.4 Kenalog-40 40 0.04

[0012] As taught by Atzinger et al., megestrol acetate suspensionsprepared using polysorbate concentrations as indicated above are notstable in that deflocculation and caking occurs. Therefore, they statethat in order to achieve a stable flocculated megestrol acetatesuspension, polysorbate must be used at a concentration at about or lessthan 0.02% w/v, preferably from 0.005% to 0.015% w/v and most preferably0.01% w/v, in combination with polyethylene glycol. At polysorbate 80concentrations as low as 0.025% w/v, there is significant deflocculationand caking. They also state that at polysorbate concentrations at orbelow 0.005-0.01% w/v, a physically stable product was obtained butthere is increased difficulty with respect to wetting of the micronizedmegestrol acetate at these low concentrations. Atzinger at al. furtherstate that only surfactants having properties similar to polysorbate 80can also be used. In this regard, they list polysorbate 20, 40, 60, 65and 85 as having acceptable wetting properties.

[0013] Surprisingly, the present invention provides for differentformulations of flocculated megestrol acetate suspensions which are alsostable.

SUMMARY OF THE INVENTION

[0014] It is, therefore, an object of the invention to provide a liquidcomposition of megestrol acetate in the form of a flocculatedsuspension.

[0015] In one embodiment, the present invention provides an oralpharmaceutical composition in the form of a stable flocculatedsuspension in water comprising:

[0016] a) megestrol acetate;

[0017] b) at least one compound selected from the group consisting ofpolyethylene glycol, propylene glycol, glycerol, and sorbitol; and

[0018] c) a surfactant,

[0019] wherein polysorbate and polyethylene glycol are notsimultaneously present in said composition.

[0020] In another embodiment of the invention, the present inventionprovides an oral pharmaceutical composition in the form of a stableflocculated suspension in water comprising on a percent weight/volumebasis about 2-6%, preferably about 4% megestrol acetate, about0.0001-0.03% surfactant, up to about 40% of at least one compoundselected from the group consisting of polyethylene glycol, propyleneglycol, glycerol, and sorbitol, about 0.5-15% carrier and flavor, andthe remainder water.

[0021] Other objects and advantages of the present invention will becomeapparent from the following description and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0022] In accordance with the invention, a flocculated suspension ofmegestrol acetate can surprisingly be formulated in the presence of anysurfactant and at least one compound selected from the group consistingof polyethylene glycol, propylene glycol, glycerol, and sorbitol.

[0023] A suspension is made up of a particular matter suspendeduniformly in a medium but not soluble in it. Individual solute moleculesdo not bond tightly to form a cake in a flocculated suspension due tothe fact that they form an open network aggregate with many branchpoints in the primary structure which prevents individual floccules fromapproaching each other closely. Flocculated suspensions have a highsedimentation height, due to the natural tendency for an open networkaggregate to not form a cake. The resulting sediment is loosely packedand possesses a scaffold-like structure. Particles do not bond tightlyto each other and a hard, dense cake does not form. Therefore, thesediment is easy to redisperse, so as to reform the original suspension.These properties make the flocculated suspension very desirable,particularly for liquid pharmaceutical formulations.

[0024] On the other hand, in a deflocculated suspension, cakes form dueto the lack of wetting of the solute, which is particularly true forhydrophobic solutes such as megestrol. For instance, in the absence ofappropriate wetting agents, individual megestrol particles clump andcake so as to minimize energetically unfavorable interactions between ahydrophobic solute (megestrol) and the bulk water. The hydrophobicsolute packs down more over time due to the eventual release of watermolecules from the inner portion of the cake which were physicallytrapped when cake formation began. Eventually, water molecules worktheir way out and surrounding solute molecules collapse into the voidthey leave behind. When a hard cake is formed, it is difficult, if notimpossible, to redisperse.

[0025] The surfactants in a stable flocculated suspension need to beselected carefully and be used within a critical concentration rangebecause even minor changes can have an effect on the properties of sucha stable formulation. This is particularly true for megestrol acetatebecause predictability based on prior art teachings does not apply inthis case, as noted hereinabove. What is surprising about the presentinvention is that any surfactant can effectively wet megestrol acetateand together form a stable flocculated suspension in the presence of atleast one compound selected from the group consisting of polyethyleneglycol, propylene glycol, glycerol, and sorbitol.

[0026] The surfactant can be anionic, cationic or non-ionic.

[0027] Suitable cationic surfactants include for examplecetyldimethylethylammonium bromide and quaternary amines.

[0028] Suitable anionic surfactants include for example salts ofsulphonic or monoesterified sulphuric acids such as alkyl benzenesulphonate, alkyl sulphates, alkyl ether sulphates, olefin sulphonates,alkyl phenol sulphates, alkyl phenol ether sulphates, alkyl ethanolaminesulphate, alkyl ethanolamine ether sulphates, alpha sulpho fatty acidsor esters. Other suitable anionic surfactants include fatty alkylsulphosuccinates, fatty alkyl ether sulphosuccinates, acyl sarcosinates,acyl taurides, and paraffin sulphonates. The preferred anionicsurfactants are salts of alkali metals or alkaline earth metals,preferably sodium such as docusate sodium, sodium lauryl sulfate. Othersalts include ammonium, monoethanolamine, diethanolamine,triethanolamine and alkyl amines having up to 7 aliphatic carbon atoms.

[0029] Suitable non-ionic surfactants include for example alkanolamides,ethoxylated alcohols, carboxylic acids, amines, alcohol amides, alcoholphenol, glyceryl esters, sorbitan esters, polyoxyethylene esters,phosphate esters etc. The preferred non-ionic surfactants arepolysorbate, nonoxynol and polyoxyethylene glycol fatty acid esters.Amphoteric surfactants may also be used.

[0030] Wetting of a non-polar solute such as megestrol acetate takesplace because it forms an association complex through Van der Waalsinteractions with a hydrophobic moiety of the surfactant. Thiseffectively wets the material because the hydrophobic group of thesurfactant is sequestering the megestrol while the hydrophilic group ofthe surfactant is solubilized in the bulk water. What is particularlysurprising about the present invention is that any surfactant regardlessof the length of the hydrophobic contact area on its hydrophobic groupcan effectively wet megestrol acetate and together form a stableflocculated suspension if at least one compound selected from the groupconsisting of polyethylene glycol, propylene glycol, glycerol, andsorbitol is present.

[0031] In one embodiment of the present invention, the surfactant of thepresent invention has a straight carbon chain of up to 20, preferably4-20 atoms in the hydrophobic group. In a preferred embodiment, thestraight carbon chain of the surfactant is less than 10 atoms. The mostsurprising aspect of the present invention is the fact that surfactantswith such a relatively short straight chain hydrophobic group, less than10 carbon atoms in length, wet megestrol and form a stable flocculatedsuspension. Such agents would normally not be expected to effectivelywet megestrol acetate. A relatively short straight chain hydrophobicgroup such as the one on docusate (two hexyl chains, i.e. two 6 carbonlength of straight chain in the hydrophobic group) presents a very smallhydrophobic contact area with which the megestrol acetate molecule canassociate.

[0032] In another embodiment of the present invention, the concentrationof megestrol acetate in the flocculated suspension is preferably about10 to 200 mg per ml, more preferably about 20 to 60 mg per ml and mostpreferably about 40 mg per ml. It is preferred that the megestrolacetate is micronized so that 90% of the weight of particles is below 20microns and the mass median diameter is between 3.0 and 10 microns.

[0033] In yet another embodiment of the present invention, thesurfactant is docusate sodium, preferably at a concentration of about0.0001 to 0.03% weight/volume, and more preferably about 0.005 to 0.02%weight/volume.

[0034] The presence of at least one compound selected from the groupconsisting of polyethylene glycol, propylene glycol, glycerol, andsorbitol is critical to the suspendability of megestrol acetate in aflocculated composition. This compound is preferably up to 40%, morepreferably 5-30%, and most preferably 10-25% weight/volume of thecomposition. In yet another embodiment, a mixture of glycerol andsorbitol is used, preferably each at a concentration of up to about 20%,and more preferably, about 5-15% weight/volume of glycerol and about5-15% weight/volume of sorbitol.

[0035] Conventional pharmaceutical carriers can be present. Xanthan gumis preferably used as a suspending agent at about 0.1-0.35%weight/volume, and more preferably about 0.15-0.25% w/v. The use of asuspending agent maintains the megestrol acetate particles in auniformly suspended state for a longer period of time during the doseadministration period thereby permitting uniform dosing. Xanthan gum isa high molecular weight polysaccharide having thixotropic propertieswith immediate viscosity recovery.

[0036] Conventional preservatives, buffers, sweeteners and flavoringagents are employed. In this regard, citric acid and sodium citrate arepreferred as buffers, more preferably at concentrations of about 0.3%and 0.06% weight/volume, respectively. Sodium benzoate is preferred as apreservative particularly at a concentration of about 0.1-0.3%weight/volume. Sucrose is preferred as a sweetener particularly at aconcentration of about 5% weight/volume. Lemon flavor is preferred as aflavoring agents particularly at a concentration of about 0.08%weight/volume.

[0037] In a preferred embodiment, the present invention provides an oralpharmaceutical composition in the form of a stable flocculatedsuspension in water comprising on a percent weight/volume basis about 4%megestrol acetate, about 0.0001-0.030% docusate sodium, up to about 20%glycerol, up to about 20% sorbitol, about 0.1-0.35% xanthan gum, about0.1-0.3% sodium benzoate, about 0.3% citric acid, about 0.06% sodiumcitrate, about 5% sucrose, about 0.08% flavor, and the remainder water.

EXAMPLE 1

[0038] A lemon-flavored oral suspension containing 40 mg of megestrolacetate per milliliter was prepared with a list of ingredients accordingto Table 2. TABLE 2 Formulation for Megestrol Acetate SuspensionIngredients % weight/volume  1. Megestrol Acetate USP 4.000  2. GlycerolUSP 5.000  3. Sorbitol NF 15.000  4. Docusate Sodium USP 0.002  5.Xanthan Gum NF 0.250  6. Sodium Benzoate NF 0.200  7. Citric Acid USP0.300  8. Sodium Citrate USP 0.060  9. Sucrose NF 5.000 10. Lemon Flavor0.080 11. Purified Water USP 70.108

[0039] Preparation of the megestrol acetate suspension using theabove-proportional amounts of ingredients is carried out as follows.Glycerol, sorbitol and docusate sodium are combined in water to form asolution. Next, xanthan gum is added to this solution in order touniformly hydrate the gum. The citrates, sucrose, sodium benzoate, andflavor are then added to the gum dispersion and the gum slurry passedthrough a screen. Next, megestrol acetate is added to the gum dispersionto provide a uniform suspension. The entire suspension is then passedthrough a colloid mill or homogenizer to provide an oral suspensioncontaining 40 mg/ml of megestrol acetate.

EXAMPLE 2

[0040] A lemon-flavored oral suspension containing 40 mg of megestrolacetate per milliliter was prepared with a list of ingredients accordingto Table 3. TABLE 3 Formulation for Megestrol Acetate SuspensionIngredients % weight/volume  1. Megestrol Acetate USP 4.000  2. GlycerolUSP 10.00  3. Sorbitol NF 10.00  4. Polysorbate 80 0.030  5. Xanthan GumNF 0.220  6. Sodium Benzoate NF 0.200  7. Citric Acid USP 0.300  8.Sodium Citrate USP 0.060  9. Sucrose NF 5.000 10. Lemon Flavor 0.080 11.Purified Water USP 70.11

[0041] Preparation of the megestrol acetate suspension using theabove-proportional amounts of ingredients is carried out as follows.Glycerol, sorbitol and polysorbate are combined in water to form asolution. Next, xanthan gum is added to this solution in order touniformly hydrate the gum. The citrates, sucrose, sodium benzoate, andflavor are then added to the gum dispersion and the gum slurry passedthrough a screen. Next, megestrol acetate is added to the gum dispersionto provide a uniform suspension. The entire suspension is then passedthrough a colloid mill or homogenizer to provide an oral suspensioncontaining 40 mg/ml of megestrol acetate.

EXAMPLE 3

[0042] A lemon-flavored oral suspension containing 60 mg of megestrolacetate per milliliter was prepared with a list of ingredients accordingto Table 4. TABLE 4 Formulation for Megestrol Acetate SuspensionIngredients % weight/volume  1. Megestrol Acetate USP 6.000  2.polyethylene glycol 18.00  3. Docusate Sodium 0.010  4. Xanthan Gum NF0.200  5. Sodium Benzoate NF 0.200  6. Citric Acid USP 0.300  7. SodiumCitrate USP 0.060  8. Sucrose NF 5.000  9. Lemon Flavor 0.080 10.Purified Water USP 70.15

[0043] Preparation of the megestrol acetate suspension using theabove-proportional amounts of ingredients is carried out as follows.Polyethylene glycol and docusate sodium are combined in water to form asolution. Next, xanthan gum is added to this solution in order touniformly hydrate the gum. The citrates, sucrose, sodium benzoate, andflavor are then added to the gum dispersion and the gum slurry passedthrough a screen. Next, megestrol acetate is added to the gum dispersionto provide a uniform suspension. The entire suspension is then passedthrough a colloid mill or homogenizer to provide an oral suspensioncontaining 60 mg/ml of megestrol acetate.

EXAMPLE 4

[0044] Suspension Stability

[0045] The tendency of each suspension, prepared according to Examples1-3, to flocculate was assessed as follows. Each suspension is allowedto settle in a controlled environment of 40° C. and 75% relativehumidity for a period of 3 months. Following that, each of thesedimented suspensions was shaken and easily redispersed reforming theoriginal suspension.

[0046] The invention has been described in terms of preferredembodiments thereof, but is more broadly applicable as will beunderstood by those skilled in the art. The scope of the invention istherefore limited only by the following claims.

What is claimed is:
 1. An oral pharmaceutical composition in the form ofa stable flocculated suspension in water comprising: (a) megestrolacetate; (b) at least one compound selected from the group consisting ofpolyethylene glycol, propylene glycol, glycerol, and sorbitol; and (c) asurfactant, wherein polysorbate and polyethylene glycol are notsimultaneously present in said composition.
 2. The composition of claim1 , wherein the surfactant comprises a hydrophobic moiety having astraight carbon chain of up to 20 atoms.
 3. The composition of claim 2 ,wherein the straight carbon chain is less than 10 carbon atoms inlength.
 4. The composition of claim 1 , wherein the surfactant isnon-ionic.
 5. The composition of claim 4 , wherein the surfactant isselected from the group consisting of alkanolamides, ethoxylatedalcohols, carboxylic acids, amines, alcohol amides, alcohol phenol,glyceryl esters, sorbitan esters, polyoxyethylene esters and phosphateesters.
 6. The composition of claim 4 , wherein the surfactant ispolysorbate.
 7. The composition of claim 4 , wherein the surfactant ispolyoxyethylene 2, 4, 6, 8, 12, 20, 30, 40, 50, 100, or 150 stearate. 8.The composition of claim 1 , wherein the surfactant is cationic.
 9. Thecomposition of claim 8 , wherein the surfactant is selected from thegroup consisting of cetyldimethylethylammonium bromide and quaternaryamines.
 10. The composition of claim 8 , wherein the surfactant iscetyldimethylethylammonium bromide.
 11. The composition of claim 1 ,wherein the surfactant is anionic.
 12. The composition of claim 11 ,wherein the surfactant is selected from the group consisting of salts ofsulphonic acids, fatty alkyl sulphosuccinates, fatty alkyl ethersulphosuccinates, acyl sarcosinates, acyl taurides, paraffin sulphonatesand salts of alkaline earth metals.
 13. The composition of claim 11 ,wherein the surfactant is docusate sodium.
 14. The composition of claim13 , wherein the concentration of docusate sodium is about 0.0001 to0.03% weight/volume.
 15. The composition of claim 1 , wherein themegestrol acetate is micronized.
 16. The composition of claim 1 ,wherein the concentration of megestrol acetate is about 10 to 200 mg perml of said composition.
 17. The composition of claim 1 , wherein theconcentration of megestrol acetate is about 40 mg per ml.
 18. Thecomposition of claim 1 , wherein component (b) comprises a mixture oftwo compounds.
 19. The composition of claim 18 , wherein the compoundsare glycerol and sorbitol.
 20. The composition of claim 19 , wherein theconcentration of each of glycerol and sorbitol is up to about 20%weight/volume.
 21. An oral pharmaceutical composition in the form of astable flocculated suspension in water comprising on a percentweight/volume basis about 4% megestrol acetate, about 0.0005-0.030%docusate sodium, up to about 20% glycerol, up to about 20% sorbitol,about 0.1-0.35% xanthan gum, about 0.1-0.3% sodium benzoate, about 0.3%citric acid, about 0.06% sodium citrate, about 5% sucrose, about 0.08%flavor, and the remainder water.
 22. An oral pharmaceutical compositionin the form of a stable flocculated suspension in water comprising on apercent weight/volume basis about 4% megestrol acetate, about0.0005-0.030% polyoxyethylene 40 stearate, up to about 20% glycerol, upto about 20% sorbitol, about 0.1-0.35% xanthan gum, about 0.1-0.3%sodium benzoate, about 0.3% citric acid, about 0.06% sodium citrate,about 5% sucrose, about 0.08% flavor, and the remainder water.